Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Proc Natl Acad Sci U S A. 2011 May 24;108(21):8773-8. doi: 10.1073/pnas.1105941108. Epub 2011 May 9.
Activating K-RAS mutations are the most frequent oncogenic mutations in human cancer. Numerous downstream signaling pathways have been shown to be deregulated by oncogenic K-ras. However, to date there are still no effective targeted therapies for this genetically defined subset of patients. Here we report the results of a small molecule, synthetic lethal screen using mouse embryonic fibroblasts derived from a mouse model harboring a conditional oncogenic K-ras(G12D) allele. Among the >50,000 compounds screened, we identified a class of drugs with selective activity against oncogenic K-ras-expressing cells. The most potent member of this class, lanperisone, acts by inducing nonapoptotic cell death in a cell cycle- and translation-independent manner. The mechanism of cell killing involves the induction of reactive oxygen species that are inefficiently scavenged in K-ras mutant cells, leading to oxidative stress and cell death. In mice, treatment with lanperisone suppresses the growth of K-ras-driven tumors without overt toxicity. Our findings establish the specific antitumor activity of lanperisone and reveal oxidative stress pathways as potential targets in Ras-mediated malignancies.
激活的 K-RAS 突变是人类癌症中最常见的致癌突变。众多下游信号通路已被证明被致癌 K-ras 失调。然而，迄今为止，对于这一具有明确遗传特征的患者亚群，仍然没有有效的靶向治疗方法。在这里，我们报告了使用源自携带条件致癌 K-ras(G12D)等位基因的小鼠模型的小鼠胚胎成纤维细胞进行小分子合成致死筛选的结果。在筛选的超过 50,000 种化合物中，我们鉴定出了一类对表达致癌 K-ras 的细胞具有选择性活性的药物。这类药物中最有效的成员是 lanperisone，它以细胞周期和翻译独立的方式诱导非凋亡性细胞死亡。细胞杀伤的机制涉及诱导活性氧，这些活性氧在 K-ras 突变细胞中不能有效清除，导致氧化应激和细胞死亡。在小鼠中，用 lanperisone 治疗可抑制 K-ras 驱动的肿瘤生长，而无明显毒性。我们的发现确立了 lanperisone 的特异性抗肿瘤活性，并揭示了氧化应激途径作为 Ras 介导的恶性肿瘤的潜在靶点。
